Human double minute 2 (HDM2) oncoprotein is a negative regulator of the tumor suppressor protein p53. The p53 protein is a transcription factor which signals the activation of several protective genes when a cell encounters stress. The importance of p53 in this signaling process is evident in a number of solid tumors that contain defective forms of the p53 that are unable to stop cells from proliferating. In addition to inactivating mutations in p53, HDM2 may, in some cases, act as a negative regulator of p53.
There is evidence for a physical interaction between HDM2 and p53. First, cellular stress results in increased p53 activation, which in turn switches on the HDM2 gene. The resulting HDM2 protein represses p53 by inducing its degradation. The degradation is initiated by formation of an HDM2-p53 complex that results in proteosomal destruction of p53. This suggests that a HDM2-antagonist could restore p53's normal signaling functions for cell death and apoptosis.
Purification of this enzyme for structural and biochemical studies has been critical for the initiation of a structure-based drug design program. Crystals of MDM2 suitable for structure based drug design were reported by Kussie, P., et al., Science 274 (1996) 948-953. Taremi et al. (US2005/0037383) also reported crystals of HDM2 p53 binding domain. Schubert et al. (US2004/0197893) describe crystalline complexes. An effective technique in structure based drug design is the analysis of the ability of a certain inhibitor compound to dock into the binding site of the target protein and, using molecular modeling techniques, discern what modified compounds may also fit into the pocket and, thereby, inhibit activity of the target. There has been a need in the art for such crystalline complexes which can be used, for example, for the design of therapeutic inhibitors of the HDM2/p53 interaction. Such inhibitors are useful, for example, for the treatment of cancer.